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inflamed. 12 It is, however, rare for such predisposing con- ARSENIC CANCER: ditions to be effectual in breaking down the natural cancer A Case under the Care of resistance of the tissues, unless these are comparatively senile. So that the somewhat early age of many of the W. HARWOOD NUTT, M.D., CH. B. EDIN., subjects of arsenic cancer seems, not unreasonably, to suggest MEDICAL OFFICER TO THE SHEFFIELD UNION WORKHOUSE; HONORARY that the of arsenic in the skin may have MEDICAL OFFICER TO THE X RAY AND ELECTRICAL DEPARTMENT prolonged presence a on to Com. OF THE SHEFFIELD ROYAL HOSPITAL; deleterious influence its resistance cancer, parable with that exerted by senescence. A on the Parts Pathological Report Removed, The injuries just referred to are familiar enough in several BY J. M. BEATTIE, M.A. N.Z., M.D., C.M. EDIN., forms, such as mechanical (as a pipe in relation to cancer of PROFESSOR OF BACTERIOLOGY IN THE UNIVERSITY OF LIVERPOOL; the lips in smokers), chemical (as pitch in relation to cancer HONORARY CONSULTING BACTERIOLOGIST TO THE ROYAL of the skin in briquette makers), actinic (as X rays when SOUTHERN HOSPITAL, LIVERPOOL; over-applied to the skin),13 atmospheric (as sun, wind, and Together with Summaries of 30 other Collected Cases and salt spray in the skin cancer of sailors) (63). Remarks,1 In some other forms the nature of the injury is more un- BY R. J. PYE-SMITH, CH.M. SHEFF., F.R.C.S. ENG., certain, as that inflicted by soot in the development of cancer of the that caused CONSULTING SURGEON TO THE SHEFFIELD ROYAL HOSPITAL AND TO chimney-sweep’s scrotum, by THE MONTAGU HOSPITAL, MEXBOROUGH; EMERITUS PROFESSOR phimosis in the production of cancer of the penis, that pro- OF SURGERY IN THE UNIVERSITY OF SHEFFIELD. duced by cutaneous horns when ending in cancer, 11 that (Concluded from p. 216.) done by chronic or by Paget’s disease of the nipple, that due to the scars of burns, as in cases of kangri cancer, occurring in , where charcoal braziers are worn IN the the summaries of 30 collected cases preceding part over the skin of the abdomen,15 or that present in Kaposi’s of arsenic cancer were In this series there is a remark- given. disease (xerodermia pigmentosa) in its final cancerous able in of their features. In all of similarity many nearly stage. In other cases, again, the irregular growth incident them arsenic had been taken for over periods extending to advanced age seems to take the place of injury to the years, and in nearly all hyperkeratosis.was present, especially skin. in the palms and soles, and of a type often produced by In certain instances of some of these kinds of skin cancer arsenic. In half the cases the cancerous lesions fully a local condition of keratosis, often accompanied by desqua- were multiple, a fact strongly suggestive of the presence mation and pigmentation, and followed by fissure and of some and unusual or general predisposing exciting ulceration or by ulceration without fissure, commonly pre- cause. In a fourth of the cases the of the age cedes the onset of malignancy. The same is true of nearly patients did not exceed 35 years, again suggesting all the cases of arsenic cancer. It looks as if arsenic induces some cause.ll In several of the cases the use of special keratosis of the skin (as is now universally admitted),16 the arsenic had been discontinued for many years before the keratosis mechanically inducing fissures, which readily cancerous changes set in, pointing to its being an early or become infected with bacteria and then ulcerate, the ulcers remote rather than a late or final cause. In most of the finally becoming cancerous.17 cases the epitheliomatous process (which always began in The late Sir Jonathan Hutchinson repeatedly suggested that the to have started in a of in skin) appears patch keratosis, arsenic may possibly be a causative factor in forms of cancer a few cases in not apparently (though probably really) in which it has not hitherto been suspected ; and so widely in a normal skin, seldom, if ever, patch of , is this metal distributed in nature as to lend countenance to that the last-named in two- showing disease, though present the suggestion, for its occasional ingestion through food or thirds of the not a causative factor. In cases, was probably water must be possible to nearly all races of men and to one-fifth of the cases is mentioned. only pigmentation many animals. Arsenic is present in many soils and, in Lesions were situated on the the upper extremity (usually traces, in many natural mineral waters. It has occasionally hand) in nearly two-thirds of the cases, on the lower ex- been found in certain vegetable and animal tissues, though the in a fourth of the in one tremity (especially foot) cases ; probably it is not a normal constituent of either (66). So instance was the face the rest of the cases only affected, many drugs are liable to contain arsenic as an impurity divided between the trunk with the being nearly equally that it is not easy to say that any manufactured drug will neck and the external with the genital organs perineum. be free from it " (71), and that over 100 official substances The fact of the hands and feet so often affected being and preparations are included in the list for which a suggests that either trauma or the keratosis, so generally maximum contamination is to be fixed in the forthcoming present there, was a determining factor in the localisation of Pharmacopoeia. This list includes salts of ammonia, bismuth, the lesions. In the case recorded the of a principal wearing iron, lime, magnesia, potash and soda, as well as citric and wedding ring appeared to have fixed the site of the primary tartaric acids, glycerine, and glucose (72). . Although microscopical examination by competent The commonest source of this contamination is to be pathologists was not always conclusive in the early stages found in commercial sulphuric acid, which is manufactured of the cancerous and several of the process, although from arseniferous pyrites. It was the use of this acid in the cases were at one stage suspected to be syphilitic, yet sooner manufacture of invert sugar for brewing that was responsible or later, in almost every case, the microscope has confirmed for the epidemic of arsenical poisoning by beer at Manchester the clinical diagnosis of epithelioma. Excision of the cancerous lesion, or amputation of the affected part of the 12 To use the words of Mr. Victor Bonney, "Epithelial cancer is on a a of limb, was practised in two-thirds of the cases. In many never initiated normal surface, but is led up to by series inflammatory changes in the epithelial and subepithelial connective instances local recurrence followed these operations, and tissues " (62). in about a fourth of all cases ultimately took 13 See Multiple Carcinomata following Chronic X Ray Dermatitis, by to and internal Death from the disease Dr. Charles Allen Porter, Boston, Mass., with Pathological Report by place glands organs. Dr. Charles J. White, Harvard had occurred in half the cases when were University (59). already they 14 Dr. Hermann Lebert (64) collected the published cases of cutaneous recorded. Three times as many men were affected as horns (109 in number); in 13 of them (nearly 12 per cent.) epithelioma women. developed. See also Cornu Cutaneum of the Human Scalp, by Herman L. Niertert, and Edmund A. Babler, M.D. and Cutaneous to as a M.D., (58), Epithelial cancer appears attack, rule, tissues Horns, by Charles K. Roys, M.D. (60). which have been exposed for prolonged periods to frequently 15 See the account given by Dr. Theodore Maxwell in an article on and have in suffered a Epithelioma in Kashmir (22), and a similar account by Dr. E. F. repeated slight injury, consequence Neve of or become more or less (34a). depression vitality, definitely 16 Romberg (65) appears to have been the first (1851) to recognise that keratosis could be induced by arsenic. Thomas Hunt (20) had 11 But in a valuable paper (61) entitled " The Study of the Etiology of previously (1847) attributed pigmentation, in regions protected by the Cancer, based on Clinical Statistics," Dr. Isaac Levin, of New York, clothing, to the same cause. after analysing 4000 cases of cancer, reported from the hospitals in New 17 Irregularity in the epidermic overgrowth which occurs in keratosis York, Brooklyn, Baltimore, and Philadelphia, found that, although in may perhaps (?) lead in some cases to the segregation of small portions this series cancer generally occurred in persons under 35 years of age of epithelium, and so originate epithelioma before ulceration com- in the proportion of only about 12·6 per cent. of all cases, yet cancer of mences. See The Causation of Cancer, by L. B. Wilson, M.D. (80). the extremities, of which there were 206 cases, occurred in such persons So long ago as 1880 Sir Frederic Eve cited cases which " indicated that in 47 per cent., or nearly as often in those under as in those over the the border line between the so-called hypertrophies of epithelium age of 35. On the other hand, Mr. G. Lenthal Cheatle, C.B., collected (callosities, , &c.) and epithelioma was of the slightest description, cases of cancer of the and states a that the and that a continuance of the causes which rise to the former 56 hand, (34) (in private letter) " gave ages of the patients were all over 50. might lead to the latter (25). 283

in 1900. Arsenic is also present in the fumes from burning cancer of the lungs among workers in smaltine mines (78) gas-coke, and thus in the process of drying is occasionally has been thought to be due to the inhalation of the dust 23 conveyed to malt, hops, chicory, and tobacco. The epidemic (arsenide of cobalt), and cancer of the bladder among at Halifax in 1902 was shown to be due to beer made aniline workers has been attributed to the effects of the from malt contaminated in this way. Many wall-papers excretion of arsenic inhaled as vapour in the process of (not only those of green colour) contain large quantities manufacture (24). I have not met with any definite of arsenic, as do also some of the aniline dyes used statement as to the frequency of cancer among the in confectionery, and oxide of iron which is some- arsenic eaters of Styria. Probably their number is timesused to adulterate chocolate powder, anchovy sauce, small as compared with that of the sufferers from psoriasis &c. (69). who have been for years together treated with Fowler’s Coal contains arsenicated iron pyrites in various pro- solution. portions, and soot from the burning of ordinary house-coal If this wide occurrence of arsenic tends to justify the contains a large amount of arsenic,18 whilst soot formed by suggestion that it may be a frequent factor in the causation the burning of wood is said to be free from it. This fact of epithelioma, that suggestion may also find support in would appear, at first sight, to offer an explanation of the pathology and therapeutics ; for among the recognised effects restriction of chimney-sweep’s cancer of the scrotum to of arsenic on the body none perhaps are more marked than England, since in that country only was coal largely burnt those on the skin. In moderate doses it gives rise to hyper- during the last century, wood being much more commonly idrosis, pigmentation, keratosis, both diffuse and circum- used in most parts of Europe. The late Sir Henry Butlin, scribed, producing hoofs and corns, especially in the palms however, became convinced, after investigating the question and soles, with desquamation and sometimes warts in other with great care, that it was not so much the difference in regions, followed by atrophy of the papillse of the corium the character of the soot as the greater care in dress and and of the skin glands, and finally of the also. 24 cleanliness on the part of continental chimney-sweeps which "In frogs poisoned with arsenic the epidermis peels off accounted for the absence of this disease amongst them (28). very easily " (79). The external application of arsenic its But this view in no way invalidates the evidence that in various forms may also, apart from its poisonous and destruc- England the habitual contact of soot does, in some tive effects, produce dermatitis, desquamation, &C.25 The way, induce cancer of the scrotum in chimney-sweeps. therapeutic value of the drug with regard to the skin is This evidence is largely clinical," but it is confirmed seen in the treatment of psoriasis and other chronic skin by the mortality statistics of the Registrar-General, diseases. as analysed in the decennial supplements by the This pathological and therapeutic action of arsenic on the chief medical officer of the Registration Department. skin, especially on the epithelial cells, appears to depend in In the supplement to the Forty-fifth Annual Report part on the chemical affinity which exists between it and (30 years ago) Dr. Ogle stated that, according to the keratin ; and it is particularly interesting, in view of the mortality returns, "the liability of chimney-sweeps to admitted power of arsenic to induce and peripheral malignant disease is about eight times as great as the neuritis, to remember, as pointed out by the late Dr. Dixon average liability of all males," and in nearly half the cases Mann (67), that neuro-keratin is abundantly present in the the disease was situated in the region of sweep’s cancer nerves and in the white matter of the brain, and that those ("scrotum, penis, testes, and groin") (28). And in structures are capable of storing up arsenic.26 It has also the supplement to the Sixty-fifth Annual Report Dr. been suggested that as there are some remarkable simi- J. F. W. Tatham says, in reference to cancer, "chimney- larities in the chemical characteristics of arsenic and sweeps are still subject to the highest fatality from phosphorus, the former may exert its pathological, and this disease, although among several other occupations- perhaps also its therapeutic, effects by replacing the latter e.g., inn-servants in London, brewers, furriers, general in the molecular composition of protoplasm. 27 Another labourers, and seamen-the mortality does not fall far possible mode of action was pointed out by Professor Binz short of that of chimney-sweeps " (70). Table IV. in Part II. in 1879-namely, that, by their ready oxidation and reduc- of this Supplement shows that the fatality of cancer between tion respectively in the body, arsenious acid and arsenic the ages of 25 and 65 is two and a quarter times as great in acid exert on the tissues the powerful effects of nascent chimney-sweeps as in males generally.20 The proportion of oxygen (30). Thus there are several conceivable ways in cases affecting the sweep’s cancer region (I I scrotum, penis, which arsenic may act on the structures of the skin, so as testes, and groin ") 21 had also fallen in the 20 years between to break down their natural resistance to the cancerous the 45th and 65th Annual Reports from nearly half to just process. under a third of all cases. But all this is far from affording proof that arsenic is at Not only soot, but also tar and pitch, obtained by the all generally a factor in the causation of epithelioma. And fractional distillation of coal, contain arsenic, and workers there are several considerations which seem opposed to such in these substances, such as briquette makers (70), are subject a supposition. One of these is the low cancer mortality of to keratosis, melanosis, warts, ulceration, and epithelioma coal miners,2 who are constantly exposed to coal dust, of the skin. The workmen employed in refining solid though it must be remembered that the proportion of arsenic paraffin are subject to similar conditions of the skin.’2 in coal is very much less than in the soot derived from it (70). There appears to be no evidence that paraffin is liable to be Another is the existence of cases closely resembling those contaminated by arsenic, but these effects may be attribut- herein reported, but without any history, sign, or apparent able to the tar and naphtha which the men have to deal probability of arsenic having been at any time present, such with in the manufacturing process. The occurrence of as the series of 56 cases of cancer of the hand referred to by Mr. Cheatle.29 There are also the numerous cases where 18 Professor Delépine found 51/2 grains and 28 grains respectively of arsenious acid in two of coal soot per pound samples (68). 23 Sir Frederic Eve referred to this occurrence in the discussion on 19 E.g., Butlin found that 29 out of the 39 cases of scrotal cancer Sir Jonathan Hutchinson’s cases at the Pathological Society (23). admitted 20 into St. Bartholomew’s occurred in during years Hospital 24 See The Action of Arsenic on the Skin, Dr. H. G. Brooke (29). chimney-sweeps (28). by 25 Many details as to eruptions caused both by internal and by 20 Thus it appears that the cancer mortality from among chimney- external applications of arsenic are to be found in Drug Eruptions, sweeps, as compared with males generally, is not now nearly as exces- Prince A. Morrow, M.D., edited Dr. T. Colcott Fox sive as it was 30 but it must be that ever since by by (9). years ago; remembered 26 the middle of last century the percentage of registered deaths from This raises the question whether it is through the nerves rather than on the skin that arsenic acts in the of cancer in males has gone up continuously, and is now more than treble directly development and recalls the relation of skin cancers to nerve what it was 60 years ago. See chart in Vol. I. of Supplement to Sixty- cancer, areas, out Mr. Cheatle. See Note a Possible fifth Annual Report. Happily this seems to be largely accounted for by repeatedly pointed by upon between Carcinoma and Nerve or increasing exactitude in the certificates of cause of death. Lawson (21) Relationship Trophic Areas, by suggested that the discontinuance of the practice of riddling the soot G. Lenthal Cheatle, C.B. (32), and subsequent papers. (in consequence of its diminished value) has reduced the incidence of 27 Dr. H. Leslie Roberts, in a paper on the Action of Arsenic on the scrotal cancer in chimney-sweeps. Healthy Tissues of the Skin, states that "M. Bouillac has shown 21 of Chemical Part that arsenates From an point of view it seems a that the different (Journal Society, II., 1898) may etiological pity take the of in the nutrition of genital organs are not classed separately. In the Sixty-eighth Annual partially place phosphates many Report of the Registrar-General, Table K, p. cii., shows the deaths from algæ" (30). cancer in males in various parts of the body, but unfortunately it does 28 The comparative mortality figure for cancer at all ages is given in not specify the scrotum. the Sixty-fifth Annual Report of the Registrar-General (74) as being 3 136 for 51 for coal miners. 22 See Professor Volkmann, on Tar, Paraffin, and Soot Cancer (76); for all occupied males, chimney-sweeps, Dr. Joseph Bell, F.R.S.E., on Paraffin Epithelioma of the Scrotum (77); 29 Observations on the Incidence and Spread of Cancer, by G Dr. Robert Kirk, on Paraffin Cancer (33). Lenthal Cheatle, C.B. (34) 284

injuries or irritations of various kinds provide such obvious been found by the authors in tar, gas-works pitch, and causes as to exclude the suggestion of arsenic in the absence soot ; and Mr. H. C. Ross informs me that, judging by of definite evidence-e.g., the collection made by Dr. C. its action with individual cells in vitro, "arsenic is not a Labiche 30 of 29 cases of epithelioma of the hand, mostly direct auxetic, but it has slight kinetic action," and may in labourers and grooms, men whose work exposes them to thus act as an augmentor. If this work should receive con- injury and dirt, and the 11 cases of X ray cancer collected firmation and gain general acceptance, it would seem likely by Dr. Charles Allen Porter (59). Again, the frequency of to elucidate the mode of action of many reputed factors in multiplicity in the lesions, which the arsenic cancer cases the causation of cancer. have in common with the X ray cases, the cases of sailor’s The etiology of arsenic cancer points definitely to its cancer, and those of xerodermia pigmentosa, seems to prophylaxis. On the first indication of arsenical keratosis separate all these from the more ordinary cases of single the drug should be suspended, and the condition, if it epithelioma of the skin, and to point to the presence in continues, should be treated by local applications (such as them of such special etiological factors as arsenic, X rays, salicylic acid preparations or X rays) to the diffuse lesions atmospheric and solar influences. Lastly, where hyper- and carbon-dioxide snow (which Dr. Nutt found very keratosis is present we already have a condition that is succesful in our case) to the corns and warts. If a fissure well recognised as one which is frequently pre-cancerous, persists for more than a month, or if an ulcer develops, though only exceptionally referable to the effect of probably the best treatment is that advised by Dr. C. A. arsenic.31 Porter for X ray ulcers (59)-viz., erasion and skin grafting. The fact that it may not be until many years after the When once epithelioma is diagnosed (and the diagnosis drug has been discontinued that the cancerous process sets presents no special difficulty, and should not long remain in has been made an objection to admitting in any cases a doubtful) the treatment should be prompt and energetic- causal relationship of arsenic to cancer. This difficulty, wide excision or amputation-the latter being usually however, if admitted to be valid, is present also, though in required in the case of a finger, and sometimes for a hand a less degree, with regard to arsenical keratosis. In the or foot. Multiple or recurrent lesions may need manifold or principal case here reported a period of eight or nine years repeated operations. The prognosis is apparently at least as was apparently required for the development of keratosis bad as it usually is in cases of epithelioma of the skin. after the arsenic had ceased to be taken, a further period Whether or not the existence of this group of cases is of six years elapsing before cancer commenced. Whether capable of throwing any light on the problem of the cause or not it is possible for the arsenic which has become fixed of cancer, its recognition may at least serve to warn us in the keratin of the cuticle to continue to affect the deeper of a danger attaching to the prolonged administration of layers of the epidermis, it must not be forgotten that it may arsenic. be stored up also in vascular structures, such as the white matter of the brain and the whence it be References.-1. Transactions of the Pathological Society of London, (67) thyroid, 32 may vol. xxxix., p. 352. 2. Transactions of the Clinical Society, vol. xxvii., transferred by the blood to the skin so slowly that years p. 102. 3. Transactions of the American Dermatological Association, may conceivably be occupied in the process. 1899, p. 11. 4. Ibid., 1899, p. 18. 5. Ibid., 1906, p. 144. 6. Ibid., 1908, p. 222. 7. American Journal of the Medical Sciences, vol. lxxxix., It seems, therefore, reasonable to conclude that, whilst p. 163. 8. Ibid., vol. cxviii., p. 265. 9. New Sydenham Society, arsenic plays a definite part as an indirect etiological factor vol. cxliii., p. 355. 10. Ibid., vol. clxx., p. 233. 11. Ibid., vol. clxx., in the small group of cases of so-called arsenic cancer, there p. 257. 12. Ibid., Atlas of Clinical Medicine, Surgery and Pathology, vol. 71. 13. Archives of vol. 14. vol. is no of its of in the i., p. Surgery, v., p.339. Ibid., ix., probability being etiological importance pp. 63, 223. 15. Ibid., vol. ix., p. 224. 16. The Polyclinic, vol. vi., great majority of cases of epithelioma of the skin, and still p. 336. 17. Ibid., vol. vi., p. 386. 18. Ibid., vol. vi., p. 584. 19. Medical less in cancer generally. Arsenic cannot be regarded as the Review, vol. v., p. 524. 20. THE LANCET, vol. i., 1847, p. 91. 21. Ibid., vol. 22. vol. 152. 23. vol. essential and efficient cause, without which cancer cannot ii., 1878, p. 576. Ibid., i., 1879, p. Ibid., ii., 1887, p. 1166. 24. Ibid., vol. ii., 1898, p. 1672. 25. British Medical occur, but it may well be one of many predisposing or Journal, vol. ii., 1880, p. 387. 26. Ibid., vol. ii., 1887, pp. 163, 229. contributory causes. 27. Ibid., vol. ii., 1887, p. 1280. 28. Ibid., vol. i., 1892, p. 1341, and 29. The real cause of cancer is to seek. the latest vol. ii., 1892, pp. 1, 66. Ibid., vol. ii., 1901, p. 860. yet Among 30. Ibid., vol. ii., 1901, p. 861. 31. Ibid., vol. ii., 1901 p. 864. on there is one a hypotheses the subject which offers bio- 32. Ibid., vol. i., 1903, p. 904. 33. Ibid., vol. ii., 1903, p. 1528. 34. Ibid., chemical explanation of the cancer-inducing properties of vol. i., 1908, p. 437. 34a. Ibid., vol. ii., 1910, p. 589. 35. Ibid., soot, tar, &c., other than their arsenic. vol. i., 1911, p. 977. 36. Ibid., vol. ii., 1912, pp. 97, 727; vol. i., pitch, containing 1913, p. 681. 37. Journal of Cutaneous Diseases (New York), vol. xxv., In the McFadden researches into the cause of cancer (81) p. 26. 38. Ibid., vol. xxvii., p. 130. 39. Ibid., vol. xxx., p. 192. 40. the view is put forward that cancer is "due to a combina- Treizième Congrès International de Médecine (Paris, 1900), Section de tion of two factors-local with the of Dermatologie, Comptes Rendus, tome ix., p. 221. 41. Annales de injury, production Dermatologie et de Syphilographie, 3me série, tome v., p. 234. 42. auxetics," and the simultaneous absorption of augmentors Ibid., 3me série, tome viii., p. 586. 43. Ibid., 3me série, tome viii., by the cells. Auxetics are defined as chemical sub- p. 916. 44. Ibid., 3me série, tome ix., p. 481. 45. Ibid., 4me série, 4me 47. stances the amidine some of which tome iii., p. 1121. 46. Ibid., série, tome iv., p. 412. Ibid., containing grouping, 5me série, tome i., p. 65. 48. Ibid., 5me série, tome iii., p. 129. 49. (natural auxetics-e.g. creatine and tyrosine) are set Archiv für Dermatologie und , Band xliii., p. 221. 50. Monats- free by the death of protoplasm, whilst others (artificial hefte für praktische Dermatologie, Band viii., p. 1. 51. Allgemeine de la theobromine and are of different Wiener Medizinische Zeitung, Band ii., p. 59. 52. Bulletin auxetics, e.g., allantoin) Société de tome 587. 53. Ibid., 4me and which all have the of cell Anatomique Paris, 3me serie, ix., p. origins, power causing serie, tome ii., p.549. 54. Gazette des Hôpitaux, 1878, p. 750. 55. division and reproduction, exerting this power in normal Semaine Médicale, 1902, Dec. 10th. 56. Bulletins et Mémoires de la growth, in healing, and in benign tumour growth. Aug- Société de Chirurgie de Paris, tome iii., p. 351. 57. Treatise on Diseases of the Skin, by W. H. Stelwagon, M.D., sixth edition, 1910, p. 851. 58. mentors are alkaloidal substances (kinetics) (natural, Annals of Surgery, vol. xliii., p. 907. 59. Ibid., vol. xlvi., p. 649. 60. produced in the body by bacterial putrefaction-viz., Ibid., vol. xlvi., p. 674. 61. Ibid., vol. li., p. 768. 62. The Practi- cadaverine and choline, 33 and artificiaf, e.g., atropine tioner, 1912, p. 529. 63. Histopathology of the Diseases of the and other when added Skin, by Professor Unna, translated by Dr. Norman Walker, 1896, vegetable alkaloids), which, to them, p. 719. 64. Ueber Keratose, by Dr. Hermann Lebert, 1864, p. 85. greatly increase the action of the auxetics. The hypothesis 65. Klinische Wahrnehmungen und Beobachtungen, 1851, p. 228. is that " cancerous proliferation is immediately brought 66. Report of Royal Commission on Arsenical Poisoning, 1903, Minutes of Evidence, vol. answers 2307, 3789. 67. vol. answer 3737. about the causes of normal cell i., Ibid., i., by proliferation (auxetics) answer " 68. Ibid., vol. i., 5247. 69. Ibid., vol. ii., Appendix 27. 70. Ibid., ,vlits augmentors." Both auxetics and augmentors have vol. ii., Appendix 30, and elsewhere. 71. Report and Recommendations with Reference to the Tests for the Detection of Arsenic in the Drugs 30 Thèse de Faculté de Paris, 1897 (43). of the British Pharmacopoeia, by Professor W. R. Dunstan, F.R.S., and Dermatologie, H. H. 13. 72. of the 31 Professor W. at the International Robinson, F.C.S., 1904, p. Supplementary Report Dubreuilh, Twelfth Congress Committee of Reference in to the Committee of Medicine in the name Pharmacy Pharmacopoeia 1896, proposed "pre-cancerous keratoses" of the General Medical Council, 1912. 73. to the for such conditions as " senile senile the Supplement Sixty- horns, keratosis, hyper- fifth Annual of the Part cvi. 74. Ibid., keratosis of xeroderma arsenical keratosis, the warts of Report Registrar-General, II., p. pigmentosum, Part II., Table V. 75. on Ulceration of the Skin and and and the of mucous Special Report Epi- chimney-sweeps paraffin workers, theliomatous Cancer in the Manufacture of Patent Fuel and membranes."-" De la Mélanose Circonscrite of Grease, Précancéreuse"(48). by T. M. M.D., H.M. Medical Inspector of Factories, Home Dr. H. Legge, 32 See analysis by M. Armand Gautier, quoted by Leslie office, 1910. 76. Beiträge zur Chirurgie, 1875, p. 370. 77. Edinburgh Roberts (30). Medical Journal, vol. xxii., p. 135. 78. Ore and Stone Mines, by C. 33 On the other hand, choline has been used with encouraging Le Neve Foster, p. 686. 79. Materia Medica, Pharmacy, Pharmacology, results in the treatment of cancer by Professor Werner at the and Therapeutics, by W. Hale White, M.D., twelfth edition, 1911, Heidelberg Cancer Institute, at whose head is Professor Czerny (36). p. 222. 80. Collected Papers by the Staff of St. Mary’s Hospital, Similarly arsenic has often been credited with curative properties in Rochester, U.S.A., The Mayo Clinic, 1911, p. 532. 81. Researches into cases of cancer, a possibility by no means incompatible with its being, Induced Cell-reproduction and Cancer, by H. C. Ross, M.R.C.S., in other cases, a factor in inducing the disease. X rays are capable of L.R.C.P., J. W. Cropper, M.B., M.Sc., and E. H. Ross, M.R.C.S., both causing and curing cancer, and the effects of drugs (as, indeed, of L.R.C.P., 4 vols., 1910-11-12-13. 82. Proceedings of the Royal Society actions in general) may be good or bar according to circumstances. of Medicine, vol. vi., Clinical Section, p. 229.